Organic synthesis reactions on-water at the organic-liquid water interface

Organic reactions that occur at the water interface for water-insoluble compounds, and reactions in water solution for water soluble compounds, has added a powerful dimension to prospects for organic synthesis under more beneficial economic and environmental conditions. Many organic molecules are partially soluble in water and reactions that appear as heterogeneous mixtures and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water molecules and organic molecules at this interface is discussed in the light of reported theoretical and experimental studies. The on-water catalytic effect, relative to neat reactions or organic solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compounds. In some cases when on-water reactions produce quantitative yields of water-insoluble products they can reach ideal synthetic aspirations

Research data supporting "A fragment profiling approach to inhibitors of the orphan M. tuberculosis P450 CYP144A1"

Fragment-based approaches to targeting CYP144 from Mycobacterium tuberculosi

Insight into Protein Conformation and Subcharging by DMSO from Native Ion Mobility Mass Spectrometry

Electrospray ionization-mass spectrometry (ESI-MS) interfaced with ion-mobility (IM) spectrometry has enabled the study of protein structure and interactions under native-like conditions. In biological assays, dimethyl sulfoxide (DMSO) is often included as a co-solvent to dissolve organic molecules. While low levels of DMSO are known to reduce the charge of protein ions generated by ESI, the exact mechanism by which this occurs has been debated. In this study, we describe the first application of IM–MS to study the effect of DMSO subcharging on native protein conformation. We find that at low concentrations, DMSO induces modest (1-2 %), but repeatable, reductions in protein collision-cross sections (CCSs) of four different protein complexes, avidin, concanavalin A, alcohol dehydrogenase, and pyruvate kinase, as measured by traveling-wave (TW) IM–MS. Individual protein charge states also experienced compaction in size, suggesting that this effect could not be attributed to the shift of charge state distribution by DMSO alone.D.S.-H. Chan acknowledges the support of the Croucher Foundation and the Cambridge Commonwealth, European and International Trust for receipt of a Croucher Cambridge International Scholarship

Can computational efficiency alone drive the evolution of modularity in neural networks?

Some biologists have abandoned the idea that computational efficiency in processing multipart tasks or input sets alone drives the evolution of modularity in biological networks. A recent study confirmed that small modular (neural) networks are relatively computationally-inefficient but large modular networks are slightly more efficient than non-modular ones. The present study determines whether these efficiency advantages with network size can drive the evolution of modularity in networks whose connective architecture can evolve. The answer is no, but the reason why is interesting. All simulations (run in a wide variety of parameter states) involving gradualistic connective evolution end in non-modular local attractors. Thus while a high performance modular attractor exists, such regions cannot be reached by gradualistic evolution. Non-gradualistic evolutionary simulations in which multi-modularity is obtained through duplication of existing architecture appear viable. Fundamentally, this study indicates that computational efficiency alone does not drive the evolution of modularity, even in large biological networks, but it may still be a viable mechanism when networks evolve by non-gradualistic means

Variations on a theme: diversification of cuticular hydrocarbons in a clade of cactophilic Drosophila

<p>Abstract</p> <p>Background</p> <p>We characterized variation and chemical composition of epicuticular hydrocarbons (CHCs) in the seven species of the <it>Drosophila buzzatii </it>cluster with gas chromatography/mass spectrometry. Despite the critical role of CHCs in providing resistance to desiccation and involvement in communication, such as courtship behavior, mating, and aggregation, few studies have investigated how CHC profiles evolve within and between species in a phylogenetic context. We analyzed quantitative differences in CHC profiles in populations of the <it>D. buzzatii </it>species cluster in order to assess the concordance of CHC differentiation with species divergence.</p> <p>Results</p> <p>Thirty-six CHC components were scored in single fly extracts with carbon chain lengths ranging from C₂₉to C₃₉, including methyl-branched alkanes, <it>n</it>-alkenes, and alkadienes. Multivariate analysis of variance revealed that CHC amounts were significantly different among all species and canonical discriminant function (CDF) analysis resolved all species into distinct, non-overlapping groups. Significant intraspecific variation was found in different populations of <it>D. serido </it>suggesting that this taxon is comprised of at least two species. We summarized CHC variation using CDF analysis and mapped the first five CHC canonical variates (CVs) onto an independently derived <it>period </it>(<it>per</it>) gene + chromosome inversion + mtDNA COI gene for each sex. We found that the COI sequences were not phylogenetically informative due to introgression between some species, so only <it>per </it>+ inversion data were used. Positive phylogenetic signal was observed mainly for CV1 when parsimony methods and the test for serial independence (TFSI) were used. These results changed when no outgroup species were included in the analysis and phylogenetic signal was then observed for female CV3 and/or CV4 and male CV4 and CV5. Finally, removal of divergent populations of <it>D. serido </it>significantly increased the amount of phylogenetic signal as up to four out of five CVs then displayed positive phylogenetic signal.</p> <p>Conclusions</p> <p>CHCs were conserved among species while quantitative differences in CHC profiles between populations and species were statistically significant. Most CHCs were species-, population-, and sex-specific. Mapping CHCs onto an independently derived phylogeny revealed that a significant portion of CHC variation was explained by species' systematic affinities indicating phylogenetic conservatism in the evolution of these hydrocarbon arrays, presumptive waterproofing compounds and courtship signals as in many other drosophilid species.</p

Structural Characterization and Ligand/Inhibitor Identification Provide Functional Insights into the Mycobacterium tuberculosis Cytochrome P450 CYP126A1

The Mycobacterium tuberculosis H37Rv genome encodes 20 cytochromes P450, including P450s crucial to infection and bacterial viability. Many M. tuberculosis P450s remain uncharacterized, suggesting that their further analysis may provide new insights into M. tuberculosis metabolic processes and new targets for drug discovery. CYP126A1 is representative of a P450 family widely distributed in mycobacteria and other bacteria. Here we explore the biochemical and structural properties of CYP126A1, including its interactions with new chemical ligands. A survey of azole antifungal drugs showed that CYP126A1 is inhibited strongly by azoles containing an imidazole ring but not by those tested containing a triazole ring. To further explore the molecular preferences of CYP126A1 and search for probes of enzyme function, we conducted a high throughput screen. Compounds containing three or more ring structures dominated the screening hits, including nitroaromatic compounds that induce substrate-like shifts in the heme spectrum of CYP126A1. Spectroelectrochemical measurements revealed a 155-mV increase in heme iron potential when bound to one of the newly identified nitroaromatic drugs. CYP126A1 dimers were observed in crystal structures of ligand-free CYP126A1 and for CYP126A1 bound to compounds discovered in the screen. However, ketoconazole binds in an orientation that disrupts the BC-loop regions at the P450 dimer interface and results in a CYP126A1 monomeric crystal form. Structural data also reveal that nitroaromatic ligands "moonlight" as substrates by displacing the CYP126A1 distal water but inhibit enzyme activity. The relatively polar active site of CYP126A1 distinguishes it from its most closely related sterol-binding P450s in M. tuberculosis, suggesting that further investigations will reveal its diverse substrate selectivity.This work was supported by Biotechnology and Biological Research Council (BBSRC) Grants BB/I019227/1 (to A. W. M.) and BB/I019669/1 (to C. A.) underpinning this research program and supporting the research of A. J. C. and K. J. M

A Model-Based Analysis of Chemical and Temporal Patterns of Cuticular Hydrocarbons in Male Drosophila melanogaster

Drosophila Cuticular Hydrocarbons (CH) influence courtship behaviour, mating, aggregation, oviposition, and resistance to desiccation. We measured levels of 24 different CH compounds of individual male D. melanogaster hourly under a variety of environmental (LD/DD) conditions. Using a model-based analysis of CH variation, we developed an improved normalization method for CH data, and show that CH compounds have reproducible cyclic within-day temporal patterns of expression which differ between LD and DD conditions. Multivariate clustering of expression patterns identified 5 clusters of co-expressed compounds with common chemical characteristics. Turnover rate estimates suggest CH production may be a significant metabolic cost. Male cuticular hydrocarbon expression is a dynamic trait influenced by light and time of day; since abundant hydrocarbons affect male sexual behavior, males may present different pheromonal profiles at different times and under different conditions

Slip-Sliding Away: Serial Changes and Homoplasy in Repeat Number in the Drosophila yakuba Homolog of Human Cancer Susceptibility Gene BRCA2

Several recent studies have examined the function and evolution of a Drosophila homolog to the human breast cancer susceptibility gene BRCA2, named dmbrca2. We previously identified what appeared to be a recent expansion in the RAD51-binding BRC-repeat array in the ancestor of Drosophila yakuba. In this study, we examine patterns of variation and evolution of the dmbrca2 BRC-repeat array within D. yakuba and its close relatives. We develop a model of how unequal crossing over may have produced the expanded form, but we also observe short repeat forms, typical of other species in the D. melanogaster group, segregating within D. yakuba and D. santomea. These short forms do not appear to be identical-by-descent, suggesting that the history of dmbrca2 in the D. melanogaster subgroup has involved repeat unit contractions resulting in homoplasious forms. We conclude that the evolutionary history of dmbrca2 in D. yakuba and perhaps in other Drosophila species may be more complicated than can be inferred from examination of the published single genome sequences per species